Immune modulation mechanism mediated by poxvirus IL-18 binding protein

描述(申请人提供)：致病性天花病毒和猴痘病毒对当今大部分未接种疫苗的人群构成危险威胁，而减毒的天花病毒作为疫苗载体有很大的前景。抗痘病毒疗法和更好的基于痘病毒的疫苗的需要要求对痘病毒如何调节宿主免疫反应有更深入的了解。这项提议的重点是一种有效的白介素18(IL-18)抑制物，它由多种天花病毒、猴痘病毒和牛痘病毒分泌。IL-18是一种多效性细胞因子，可增强先天免疫和后天免疫[1，2]。在小鼠模型中，它可以预防微生物感染和肿瘤。许多痘病毒表达一种IL-18结合蛋白(IL-18BP)，与IL-18高亲和力结合并抑制IL-18介导的免疫反应[3-5]。这一建议背后的中心假设是，痘病毒IL-18BP极大地影响痘病毒的致病性和免疫原性，全面了解IL-18BP的作用机制和体内效应将导致治疗痘病毒疾病的新方法和更好的基于痘病毒的疫苗。我们的具体目标是：1.进一步确定IL-18BP结合和抑制IL-18的分子机制。在分子水平上详细了解IL-18、IL-18BP和IL-18受体之间的特异性相互作用，将有助于开发针对IL-18BP和IL-18的特异性抑制剂，用于治疗感染性和炎症性疾病。2.研制抗痘病毒IL-18BP的抑制剂，并评价其降低痘病毒致病性的作用。目的：确定痘病毒IL-18BP在痘病毒致病过程中的空间需求。3.探讨IL-18BP在痘病毒疫苗免疫原性中的作用。这将使人们更好地了解IL-18在保护性免疫反应发展中的作用，并有助于开发更安全和更具免疫原性的疫苗载体。公共卫生相关性：抗痘病毒疗法和更好的基于痘病毒的疫苗的需要要求对痘病毒如何调节宿主免疫反应有更深入的了解。这项提议的重点是一种有效的白介素18(IL-18)抑制物，它由多种天花病毒、猴痘病毒和牛痘病毒分泌。全面了解IL-18BP的作用机制和体内作用，将为痘病毒病的新疗法和更好的痘病毒疫苗奠定基础。

DESCRIPTION (provided by applicant): Pathogenic poxviruses such as variola virus and monkeypox virus pose a dangerous threat to today's largely unimmunized population, while attenuated poxviruses hold great promise as vaccine vectors. The need for both anti-poxvirus therapies and better poxvirus-based vaccines demands a deeper understanding of how poxviruses modulate the host immune responses. The focus of this proposal is on a potent interleukin-18 (IL- 18) inhibitor that is secreted by a wide variety of poxviruses, including variola virus, monkeypox virus and vaccinia virus. IL-18 is a pleiotropic cytokine that enhances both the innate and acquired immunity [1, 2]. It protects against microbial infection and tumors in murine models. Many poxviruses express an IL-18 binding protein (IL-18BP) that binds to IL-18 with high affinity and inhibits IL-18 mediated immune responses [3-5]. The central hypotheses behind this proposal are that poxvirus IL-18BP greatly affects poxvirus pathogenicity and immunogenicity and that a comprehensive understanding of IL-18BP functioning mechanism and in vivo effects will lead to new therapies for poxvirus diseases and better poxvirus- based vaccines. Our specific aims are: 1. To further determine the molecular mechanism by which IL-18BP binds and inhibits IL-18. A detailed understanding of the specific interactions between IL-18, IL-18BP and IL-18 receptor at the molecular level will greatly benefit the development of specific inhibitors against IL-18BP and IL-18 for the treatment of infectious and inflammatory diseases. 2. To develop inhibitors against poxvirus IL-18BP and evaluate the effects of these inhibitors at reducing poxvirus pathogenicity. To determine the spatial requirement of poxvirus IL-18BP in poxvirus pathogenesis. 3. To determine the role of IL-18BP in immunogenicity of poxvirus-based vaccine. This will allow a better understanding of the role of IL-18 in the development of protective immune responses and facilitate the development of a safer and more immunogenic vaccine vector. PUBLIC HEALTH RELEVANCE: The need for both anti-poxvirus therapies and better poxvirus-based vaccines demands a deeper understanding of how poxviruses modulate the host immune responses. The focus of this proposal is on a potent interleukin-18 (IL-18) inhibitor that is secreted by a wide variety of poxviruses, including variola virus, monkeypox virus and vaccinia virus. A comprehensive understanding of IL-18BP functioning mechanism and in vivo effects will lead to new therapies for poxvirus diseases and better poxvirus-based vaccines.